Project 3 will use the hu-PBL-SCID model and a modified hu-PBL/skin-SCID mouse model to evaluate the antiviral activity of PSC- and other modified RANTES compounds following systemic or topical administration. Dose ranging studies of PSC-RANTES and fusion inhibitors alone and in combination will be tested for inhibition of R5 HIV-1 infection in the hu-PBL-SCID model. The activity of fusion inhibitors should be augmented by blocking CCR5 expression, since the reduction in co-receptor expression will provide fewer fusion intermediates to inhibit. It will be determined if suboptimal concentrations of PSC-RANTES can select for RS to X4 co-receptor switch variants (as occurred with NNY-RANTES) in the hu-PBL-SCID model. If such escape variants are observed, the ability of combination therapy with fusion inhibitors together with PSC-RANTES to prevent their emergence will be tested. Models for T lymphocyte recruitment to human skin grafts placed on hu- PBL-SCID will be generated and evaluated. Human T cells are known to migrate to sites of intradermal RANTES injection into human skin grafts on hu-PBL-SCID mice, and experiments will determine if PSC-RANTES has agonist or antagonist activity in such assays. A transepithelial model for HIV-1 transmission will be developed by direct application of virus to human skin grafts with the stratum corneum removed, and PSC-RANTES and fusion inhibitors will be evaluated for interference with transmission.